Scientific evidence continues to support vascular contributions to cognitive impairment and dementia (VCID) such as Alzheimer's disease (AD). In fact, ~50% of dementia patients have mixed vascular and AD pathologies in their brains. Among many potential clinical triggers, multi-embolic infarcts and cerebral hypoperfusion, especially in the presence of aging and hypertension, are major vascular factors in VCID, referred as vascular dementia (VaD), but underlying mechanisms remain elusive. Notably, neurofibrillary tangles composed of hyperphosphorylated tau are a neuropathological hallmark of AD, but pure VaD human brains do not have obvious tau tangle pathology so that little is known about the role of tau pathology in the development of VaD. Recently, we have identified a unique prolyl isomerase, Pin1 that prevents accumulation of the phosphorylated Thr231-Pro motif in tau (P-tau) in the pathogenic cis conformation, but is inactivated in AD by aging, oxidation and others. Cis P-tau is a previously unknown precursor of tau pathology that instigates and propagates neurodegeneration and dementia associated with AD and traumatic brain injury (TBI), but can be blocked by cis mAb. In our pilot studies, we found robust cis P-tau in neurovascular unit cells without tau tangle pathology in pure VaD human brains and mouse models after multi-embolic infarcts or cerebral hypoperfusion. Furthermore, purified cis P-tau was toxic both to neurons and brain microvascular endothelial cells and also caused brain dysfunction in mice, both of which were effectively blocked by cis mAb. Moreover, cis mAb blocked hypoxia or serum depletion from inducing cis P-tau and cell death in vascular endothelial cells and neurons in vitro and restored white and gray matter lesions and neurologic deficits after repetitive TBI in mice. In this proposal, we have assembled a team with all the requisite expertise to test our novel hypothesis that during aging, vascular insults lead to oxidative stress that inactivates Pin1, resulting in accumulation of cis P-tau that damages the neurovascular unit, thereby serving as an early and druggable driver of VaD. We will first assess Pin1 inhibition and cis P-tau induction in different neurovascular unit cells, and their relationships with vascular pathology and white matter lesions in VaD human brains and after multi-embolic infarcts or cerebral hypoperfusion in young and old mice with or without hypertension or Pin1 knockout. We will then purify cis P-tau proteins from VaD human brains and VaD mouse brains to characterize their biochemical property and ability to damage neurovascular unit cells in vitro and in vivo to induce white matter lesions and neurologic deficits relevant to VaD. Finally, we will evaluate the efficacy of cis mAb in inhibiting neurovascular unit damage in vitro and restoring white matter lesions, delayed neurodegeneration and neurologic deficits after multi-embolic infarcts or cerebral hypoperfusion in aged hypertensive or Pin1 knockout mice. These studies should help us identify cis P-tau as an early disease driver of VCID, uncover a common molecular mechanism underlying vascular and AD pathologies, and pursue targeted therapy for these major diseases.